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Background

The optimal sequencing of breast irradiation and adjuvant systemic therapy is controversial. A randomized trial evaluating the sequencing of radiation and cytotoxic chemotherapy trended toward more distant recurrence in patients treated with radiation first. A similar question exists regarding the sequencing of adjuvant hormonal therapy and radiation. Concurrent tamoxifen with radiation has been associated with more radiographic (but not clinical) findings of lung toxicity. Although tamoxifen can induce G1 arrest, a relatively radio-resistant phase of the cell cycle, experiments in cell culture have not consistently shown either a strong radio-protective or a radiosensitizing effect. Three retrospective studies examining sequencing of tamoxifen and radiation were published back-to-back in the Jan 2005 issue of J Clin Oncol.

Methods

- Design: Retrospective analysis of breast cancer patients treated at the University of Pennsylvania

Results

The sequential and concurrent patient groups were generally similar except the concurrent group was older (median age 59 vs. 51) and received less chemotherapy (25 v. 63%). Of note, similar trends were seen in the accompanying paper by Ahn et al.

Local failure rates at 5 and 10 years were: 2% and 3% for concurrent; 2% and 7% for sequential

Relapse-free survival rates at 5 and 10 years were: 92% and 85% for concurrent; 89% and 76% for sequential

Overall survival rates at 5 and 10 years were: 94% and 81% for concurrent; 90% and 86% for sequential

Multivariate analysis adjusting for age and use of chemotherapy showed a hazard ratio for local recurrence of 1.23 (95% CI, 0.33 to 4.49). Hazard ratios for relapse-free and overall survival were 1.22 and 1.56, respectively, with 95% CI encompassing 1.0, consistent with no statistical difference between the groups.

Complications: breast edema, arm edema, pneumonitis, and rib fractures were not different between the groups, although complications were generally rare. Cosmesis was also similar with 94% of both groups having good or excellent cosmesis.

Discussion

There was no difference in local recurrence, relapse-free survival, overall survival, cosmesis, or adverse complications between women treated with either sequential of concurrent tamoxifen and radiation. This is similar to the results reported in the two other papers published in the same issue of JCO (by Ahn et al and Pierce et al). Amongst the three studies, a strength of this paper was the reporting of complications and cosmesis.

The authors contend that either concurrent or sequential tamoxifen and radiation are reasonable to use.

In regards to timing tamoxifen with systemic chemotherapy, concurrent tamoxifen was associated with an increased rate of thromboembolic events and worse disease-free survival (67 vs 62%, p=0.045). Therefore, tamoxifen should not be given concurrently with chemotherapy.

Comments

All three of the retrospective studies addressing this question are limited by size and the fact that they are not prospective, randomized trials. Nonetheless, none of three detected a clinically significant effect in regards to timing. A "mini" meta-analysis of these studies was reported in a letter to the editor (JCO 23:6266). The overall hazard ratio for local recurrence was 0.91 (95% CI, 0.52 – 1.61).

The decision to use concurrent vs. sequential tamoxifen and radiation can be made according to other patient factors. In regards to patient quality of life during treatment, sleep disturbances associated with a course of radiation therapy may be compounded by side effects of tamoxifen (hot flashes, etc.).

These papers stimulated a flurry of letters to the editor, debating the need for a randomized controlled trial to test this question directly. As one correspondent noted, the sequencing with tamoxifen may be less relevant as aromatase inhibitors become the adjuvant hormonal treatment of choice.